Calcineurin inhibition deactivates pyruvate dehydrogenase and induces proximal tubule cell metabolic dysfunction,...

Area of Science:

• Nephrology
• Immunology
• Molecular Biology

Background:

• Calcineurin inhibitors (CNIs) are vital immunosuppressants but cause nephrotoxicity and kidney fibrosis.
• The precise mechanism linking calcineurin inhibition to kidney fibrosis is not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which calcineurin inhibition leads to kidney fibrosis.
• To identify potential therapeutic targets for mitigating CNI-induced nephrotoxicity.

Main Methods:

• Single-nucleus RNA sequencing in a chronic CNI nephrotoxicity mouse model.
• In vitro studies using primary human renal proximal tubule epithelial cells.
• Pharmacological activation of pyruvate dehydrogenase in cell culture and in vivo.

Main Results:

• CNI treatment increased injured proximal tubule cells with altered gene expression related to metabolism, senescence, and fibrosis.
• CNIs deactivated pyruvate dehydrogenase, impaired mitochondrial function, and induced senescence in human renal cells.
• Dichloroacetic acid, a pyruvate dehydrogenase activator, ameliorated CNI-induced fibrosis and transcriptional changes in mice.

Conclusions:

• Calcineurin inhibition disrupts proximal tubule cell metabolism by deactivating pyruvate dehydrogenase.
• This metabolic dysfunction promotes a profibrotic phenotype, contributing to kidney fibrosis.
• Targeting pyruvate dehydrogenase activity may offer a strategy to prevent CNI-induced nephrotoxicity.